11-119092506-G-T

Variant names:

• chr11-119092506-G-T
• NM_000190.4:c.754G>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000190.4(HMBS):​c.754G>T​(p.Ala252Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HMBS NM_000190.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.62

Genes affected

HMBS (HGNC:4982): (hydroxymethylbilane synthase) This gene encodes a member of the hydroxymethylbilane synthase superfamily. The encoded protein is the third enzyme of the heme biosynthetic pathway and catalyzes the head to tail condensation of four porphobilinogen molecules into the linear hydroxymethylbilane. Mutations in this gene are associated with the autosomal dominant disease acute intermittent porphyria. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMBS	NM_000190.4	c.754G>T	p.Ala252Ser	missense_variant	Exon 11 of 14	ENST00000652429.1	NP_000181.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HMBS	ENST00000652429.1	c.754G>T	p.Ala252Ser	missense_variant	Exon 11 of 14		NM_000190.4	ENSP00000498786.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461862 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	25
DANN	Benign	0.96
DEOGEN2	Uncertain	0.67	.;D;.;T;.;.;.;.
Eigen	Benign	-0.0027
Eigen_PC	Benign	0.16
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Uncertain	2.1	.;M;.;.;.;.;.;.
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.11	.;N;N;N;.;.;N;.
REVEL	Uncertain	0.50
Sift	Benign	0.64	.;T;T;T;.;.;T;.
Sift4G	Benign	0.77	.;T;T;T;.;.;T;.
Polyphen		0.010, 0.0080	.;B;.;B;.;.;.;.
Vest4		0.39, 0.39, 0.41, 0.38
MutPred		0.88		.;Gain of phosphorylation at A252 (P = 0.1475);.;.;.;.;.;.;
MVP		0.70
MPC		0.55
ClinPred		0.92	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.56		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.56		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-118963216;